Background: Lower limb ulcers are debilitating and associated with significant morbidity, loss of productivity and decreased the quality of life. Currently used antiseptics are cytotoxic, damage the granulation tissue and interfere in the wound healing process. Superoxidized solution is nontoxic and contains reactive oxygen species which have bactericidal and wound healing properties. Aims and Objective: To compare the microbiological response and clinical efficacy of superoxidized solution versus povidone iodine in the management of lower limb ulcers. Materials and Methods: This was a prospective randomized open label study with 68 patients randomized into two groups of 34 each. They were assessed for pain, wound size, periwound erythema, periwound edema, appearance of granulation tissue, re-epithelialization, slough, discharge, and growth on culture on day 1, 5, 9, 12, 18, and 21. Microbiological response and clinical efficacy were assessed at the end of the study. The results were assessed by descriptive methods, ANOVA, unpaired t-test, and Chi-square test. Results: The mean duration of treatment, ulcer size, pain, periwound edema, erythema, and microbial growth were significantly reduced in the superoxidized solution treated group. Early appearance of granulation tissue and re-epithelialization was noted in superoxidized group. A superior microbiological response, statistically higher cure rate and lower rates of clinical failure were also observed with superoxidized solution compared to povidone iodine. Conclusion: Superoxidized solution when compared to povidone iodine was found to significantly accelerate wound healing, reduce the signs of inflammation faster and achieve better microbiological clearance.